UDP-Glucose Ceramide Glucosyltransferase Inhibition, Immune Cell Mediation, and Endometriosis Risk: A Mendelian Randomization Study.

PURPOSE

Previous studies have reported a link between UDP-glucose ceramide glucosyltransferase (UGCG), immune regulation, and endometriosis (EM). We hypothesized that UGCG inhibitors might exert therapeutic effects on EM. Therefore, in this study, we performed a two-sample, two-step Mendelian randomization (MR) analysis modeling genetic variation of UGCG inhibitors to investigate the causal relationship between genetically determined inhibition, EM, and mediation of immune cells.

METHODS

Two-sample MR was conducted using genome-wide association study data on inhibition and EM. Furthermore, we adopted strict instrumental variable selection criteria to ensure the robustness of our results and primarily employed the inverse-variance weighted method, along with the weighted median, MR-Egger, and MR-PRESSO methods for sensitivity analyses. Additionally, a two-step MR analysis was performed to investigate the potential role of immune cells in mediating the relationship between inhibition and EM.

RESULTS

inhibition was associated with a decreased EM risk, with an odds ratio of 0.915, 95% confidence interval of 0.859-0.975, and = 0.006, demonstrating the robustness of our results and potential clinical significance of our study. Among 731 types of immune cells analyzed, 12 were significantly associated with inhibition and EM, 8 of which acted as mediators. Terminally differentiated CD4+ T cells (from the maturation stages of the T-cell panel) accounted for the highest proportion of mediating cells (26.727%), whereas immunoglobulin D (IgD) expression on IgD+ CD38 B cells (from the B-cell panel) accounted for the lowest proportion (7.816%).

CONCLUSION

Inhibiting UGCG activity may reduce the risk of EM, and immune cells may mediate this effect. Our findings provide novel insights for the development of potential therapeutic strategies for EM treatment.